Whether B cells, plasma cells and antibody (Ab) play a role in the pathogenesis of MS or its animal model, experimental autoimmune encephalomyelitis (EAE) is controversial. Myelin-specific T cells can transfer EAE to naive recipients, whereas neither B cells nor Abs can transfer EAE. Ab-producing cells are extremely numerous in most active MS lesions and increased amounts of Abs in the spinal fluid are a relatively diagnostic feature of MS. Our data indicate a critical role for B cells in EAE induced by active immunization with the extracellular 120 amino acids of myelin oligodendrocyte glycoprotein (rMOG), but not when disease is induced by a short encephalitogenic peptide (MOG35-55) in C57BL/6 (B6) mice. The hypothesis to be tested is that myelin-specific B cells and their products are critical in the pathogenesis of this model of CNS inflammatory demyelination via a role in antigen processing and presentation that focuses the immune response toward encephalitogenic epitopes of MOG. [unreadable] [unreadable] Our studies indicate that rMOG-primed wild-type (WT) B6 T cell lines do not induce EAE in B cell deficient (B-/-) B6 mice, nor do B-/- T cell lines initiated with rMOG-primed T cells transfer EAE to WT or B-/- recipients. These data suggest a complex role for B cells and their products during both the initiation and effector stages of disease. We will determine the mechanisms by which B cells act in rMOG-induced EAE, and whether B cells or Ab or both are involved. Our preliminary data indicate that B-/- mice have a broader response to rMOG, as they recognize an additional MOG-epitope by proliferation and cytokine production that WT mice do not recognize. This seems to indicate that B cells or Abs affect MOG processing and presentation to T cells. Guided by these preliminary data, the foremost candidate mechanism to be tested is whether there is a differential processing of MOG by B cells vs other APCs, and whether B cells or their products focus the immune response toward encephalitogenic epitopes of MOG. Experiments will utilize WT B6 mice, B-/- mice on a B6 background, and mice with normal B cells that do not elaborate Ab ("B6/APC"). In Aim 1, the stage(s) of EAE in which B cells play a role will be fully determined. Whether B cells play a critical role in MOG processing and presentation to activate encephalitogenic T cells, using B cells specific for myelin or irrelevant antigens, will be examined in Aim 2a, and whether myelin-specific Abs or non-specific Abs alter MOG processing will be determined in Aim 2b. The remainder of Aim 2 will focus on effects of B cells on other APCs, especially dendritic cells, and on effects of B cells on cytokine and chemokine expression. Methods to alter in humans the number and function of B cells and Abs already exist, making our results potentially applicable to MS therapy.